The present application relates to new substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of general formula I: 
wherein
X denotes a single bond, xe2x80x94Oxe2x80x94, C1-C4-alkylene, an alkylene bridge having 1 to 8 carbon atoms which may be branched or unbranched and may have one or two oxygen atom(s) anywhere in the bridge, preferably C1-C3-alkylenexe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94-CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94;
R1 denotes hydrogen, methyl, ethyl, or phenyl;
R2 denotes hydrogen or methyl;
R3 denotes hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, or methoxy;
R4 denotes hydrogen, methyl, or ethyl;
R5 denotes hydrogen, methyl, or ethyl;
R6 denotes hydrogen, methyl, or ethyl;
R7 denotes tert-butyl, cyclohexyl, phenyl optionally substituted by R9 and R10, which may be identical or different, 
R8 denotes hydrogen or C1-C4-alkyl;
Z denotes oxygen, NH, or sulfur;
R9 denotes hydrogen, methyl, fluorine, chlorine, bromine, or methoxy;
R10 denotes hydrogen, methyl, fluorine, chlorine, bromine, or methoxy;
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids such as, e.g., acid addition salts with hydrohalic acids, for example, hydrochloric or hydrobromic acids, or corresponding organic acids, for example, fumaric or diglycolic acid.
Preferred compounds of general formula I are those wherein, in the above definition R4 and R5 either both simultaneously denote methyl or independently of one another may denote hydrogen or methyl, with at least one of the substituents denoting a methyl group.
Compounds of general formula I are preferred wherein:
X denotes oxygen;
R1 denotes hydrogen, methyl or ethyl;
R2 denotes hydrogen,
R2 denotes hydrogen;
R4 denotes hydrogen or methyl;
R5 denotes hydrogen or methyl;
R6 denotes methyl;
R7 denotes phenyl;
R8 denotes hydrogen; and
R9 and R10 independently of one another denote hydrogen, methyl, fluorine or methoxy,
particularly compounds of general formula I wherein, in the above definition, R4 and R5 either both simultaneously denote methyl or independently of one another denote hydrogen or methyl, with at least one of the substituents denoting a methyl group;
The following compounds are most particularly preferred:
(xe2x88x92)-(1R,2xe2x80x3S)-2-(2xe2x80x3-benzyloxy)propyl-4xe2x80x2-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and
(xe2x88x92)-(1R,2xe2x80x3S)-2-[2xe2x80x3-(2xe2x80x2xe2x80x3,6xe2x80x2xe2x80x3-difluorobenzyl)oxy]propyl-4xe2x80x2-hydroxy-5,9,9-trimethyl-6,7-benzomorphan in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
Unless otherwise stated, the general definitions are used in the following sense:
C1-C4-alkyl or C1-C8-alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 4 or 1 to 8 carbon atom(s), which may optionally be substituted with one or more halogen atom(s)xe2x80x94preferably fluorinexe2x80x94which may be identical to or different from one another. The following hydrocarbon groups are mentioned by way of example:
methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl are preferred.
Accordingly, alkylene denotes a branched or unbranched divalent hydrocarbon bridge having 1 to 8 carbon atoms which may optionally be substituted with one or more halogen atom(s)13 preferably fluorinexe2x80x94which may be identical to or different from one another.
Alkoxy generally denotes a straight-chained or branched hydrocarbon group bound via an oxygen atom; a lower alkoxy group having 1 to 4 carbon atom(s) is preferred. The methoxy group is particularly preferred.
The compounds according to the invention may be prepared by methods known from the prior art [WO 97/06146]. The invention relates to the enantiomerically pure compounds as well as the associated racemates.
The key compounds are the nor-benzomorphans 2a to 5a, which are shown in the diagram as the corresponding (xe2x88x92)-enantiomers: 
The synthesis of 2 where R=H is described in published German Application No.: 195 28 472.
Compound 3 can be prepared analogously to compound 2. The starting compound is the piperidone 6 which occurs as an intermediate in the synthesis of 2, and which is reacted for example with an ethyltriphenylphosphonium salt instead of with the corresponding ethyl derivative - as is already known from the prior art (cf. Diagram 2). 
Compound 4 is prepared analogously to the process described in WO 97/06146 from 2-methoxybenzylcyanide 11 and 2-bromopropionic acid 12. 
In the first step, for example, 2-methoxybenzylcyanide 11 is reacted with ethyl 2-bromopropionate 12 to obtain the correspondingly substituted 3-amino-2-methylbutanoic acid ester derivative 13 (since in view of the desired end product the alcohol component of the partial ester structure is not important, any other C1-C8-alkyl ester or a benzyl ester may be used): 
In order to carry out this conversion, of the Reformatsky reaction type, an alkylhalosilane, preferably, a trialkylchlorosilane, most preferably trimethylchlorosilane - and zinc powder are placed in a solvent which is inert under the reaction conditions used, preferably an ether, or in a halohydrocarbon, most preferably dichloromethane. After this mixture has been diluted with a polar - inert - solvent, preferably a cyclic ether, most preferably tetrahydrofuran - the reaction mixture is heated - preferably to reflux temperature - and combined with a mixture of the ethyl 2-bromopropionate of general formula 3 with the o-methoxybenzylcyanide and heated further, preferably to reflux temperature. After cooling and filtering off the zinc powder, the reaction mixture is mixed with a reducing agent which is selective regarding the reduction of imino functions - preferably a complex alkali metal borohydride derivative, most preferably sodium cyanoborohydride - and then mixed with an alkanol - preferably a straight-chained or branched C1-C4-alcohol, most preferably ethanol. Then an aqueous solution of a basically reacting compound - preferably ammonia solution, most preferably with concentrated ammonia solution - is added and the organic phase of the reaction mixture is isolated. After drying and evaporation in vacuo, the residue remaining is taken up in an inert solvent - preferably in an aliphatic or aromatic hydrocarbon, most preferably in toluene - and extracted with the aqueous solution of an acid - preferably a mineral acid, most preferably 2 N hydrochloric acid. Finally the aqueous phase is made alkaline with the aqueous solution of a basically reacting compound - preferably ammonia solution, most preferably with concentrated ammonia solution - and then extracted with an organic, water-immiscible extraction agent - preferably with a halohydrocarbon, most preferably with dichloromethane. The extract thus obtained is dried and then concentrated and the 3-amino-2-methylbutanoate derivative of general formula 4 is isolated.
In the second reaction step the ethyl 3-amino-2-methylbutanoate derivative 13 thus obtained is reacted with ethyl acrylate (as, in the light of the desired end product, the alcohol component of the ester structure is not critical, any other C1-C8-alkyl ester or even a benzyl ester may be used here) to obtain the corresponding ethyl 3-(2-ethoxycarbonylethyl)-amino-2-methylbutanoate derivative 14: 
In order to carry out this Michael addition reaction the ethyl 3-amino-2-methylbutanoate derivative 13 is dissolved with the ethyl acrylate in a reaction medium which is inert under the reaction conditions - preferably in a straight-chained or branched C1-C4-alkanol, most preferably ethanol - and heated - preferably to reflux temperature. After the reaction has ended the solvent is eliminated in vacuo and the resulting ethyl 3-(2-ethoxycarbonylethyl)amino-2-methylbutanoate derivative 14 is isolated.
In the subsequent third step of the reaction the 3-(2-ethoxycarbonylethyl)amino-2-methylbutanoate derivative 14 resulting from the preceding step of the reaction is cyclized to form the corresponding piperidone derivative 15: 
In order to carry out the Dieckmann""s ester condensation type cyclization step, the 3-(2-ethoxycarbonylethyl)amino-2-methylbutanoate derivative 14 is dissolved in a solvent which is inert under the cyclization conditions - preferably in an aliphatic or aromatic hydrocarbon, most preferably in toluene - and heated to reflux temperature in the presence of a basically reacting compound, preferably an alkali metal alkoxide of a branched or unbranched C1-C4-alcohol, most preferably potassium-tert-butoxide, and the components of the reaction mixture which are volatile at these temperatures are eliminated by distillation - for example by azeotropic reaction. After the reaction has ended, the reaction mixture is hydrolyzed and mixed with the aqueous solution of an acidically reacting compound - preferably with aqueous inorganic acids, most preferably with concentrated hydrochloric acid. Then a water-immiscible extraction agent which is inert under these conditions, - preferably a dialkylether, most preferably diethylether - is added and mixed with the aqueous solution of a basically reacting compound, preferably with aqueous ammonia solution, most preferably with concentrated ammonia solution. After separation of the organic phase as well as exhaustive extraction of the aqueous phase the combined organic extracts are washed with water, dried and evaporated down in vacuo and the resulting piperidone ester is isolated.
Alternatively the Dieckmann condensation described above can also be carried out by means of titanium tetrachloride in a halogenated hydrocarbon - preferably dichloromethane [M. N. Deshmukh et al., Synth. Commun. 25 (1995) 177].
In the fourth step of the reaction the piperidone derivative (piperidone ester) thus obtained is saponified and decarboxylated under alkaline or acid conditions to form the corresponding 3-methyl-4-piperidone derivative. 
For this the piperidone ester is heated, preferably to reflux temperature, in a polar, aqueous solvent or solvent mixture - preferably in a mixture of a straight-chained or branched C1-C4-alkanol and water, most preferably in an ethanol/water mixture - with a basically or acidically reacting compound - preferably with an alkali metal hydroxide or an inorganic acid, most preferably with sodium hydroxide or if an acid is used, for example, in the presence of hydrochloric acid or sulfuric acid. After saponification has been completed the reaction medium is eliminated in vacuo and the residue is taken up in a solvent suitable for the subsequent salt formation - preferably a polar organic solvent, most preferably in acetone - and the corresponding acid addition salt is precipitated.
The subsequent Wittig reaction with methyltriphenylphosphonium bromide leads in the next step to the corresponding 4-methylene-piperidine derivative 16, which can be isolated in the form of its acid addition salt - preferably in the form of a hydrohalide, most preferably in the form of its hydrochloride. 
In order to carry out the Wittig reaction the 3-methylpiperidone derivative 15 in the form of its acid addition salt - for example as the hydrochloride - is dissolved in water and combined with a basically reacting compound or - preferably - the aqueous solution thereof, most preferably, concentrated aqueous ammonia solution is used.
The aqueous phase is extracted with an organic, water-immiscible solvent - preferably with a haloalkane, most preferably with dichloromethane. After drying and evaporation in vacuo the residue is taken up in a reaction medium which is inert under the conditions used for the Wittig reaction - preferably in a cyclic ether, most preferably in tetrahydrofuran - and combined with a Wittig reagent which generates a methylene group - preferably a methyltriphenylphosphonium halide, most preferably with methyltriphenylphosphonium bromide - in the presence of a basically reacting compound, preferably an alkali metal alkoxide, most preferably potassium tert-butoxide and - depending on the reactivity of the particular educts used - reacted at a temperature in the range from 0 to 80xc2x0 C. - preferably in a range from 20 to 60xc2x0 C. and most preferably at about 40xc2x0 C. After the reaction has ended the reaction mixture is combined with water and a water-immiscible organic solvent - preferably with a haloalkane, most preferably dichloromethane - and the organic phase is separated off. After exhaustive extraction of the aqueous phase and drying of the combined extracts, the extraction agent is eliminated, the residue is dissolved in a solvent suitable for the formation of an acid addition salt, preferably in a branched or unbranched C1-C4-alkanol, most preferably in isopropanol, and combined with a suitable acid, preferably an inorganic acid - such as, for example, a hydrohalic acid, most preferably with concentrated hydrochloric acid - and the acid addition salt of the Wittig product 16 which crystallizes out is isolated.
In the subsequent reaction step the piperidine nitrogen is formylated - for example, with n-butylformate - yielding the corresponding N-formyl-3-methyl-4-methylene-piperidine derivative: 
To do this the piperidine derivative of type 16, which can be isolated in the preceding step as for example, a hydrohalide, is first converted into the corresponding free base, for example by dissolving the piperidine derivative in water and combining it with a basically reacting compound - preferably with the aqueous solution of a basically reacting compound and most preferably with concentrated ammonia solution, and extracting the free piperidine with a organic solvent, preferably with a halogenated hydrocarbon and most preferably with dichloromethane. After the extract has been dried and the extraction agent has been distilled off the free base is taken up in an organic solvent - such as, for example, a hydrocarbon, preferably in an alkyl-aromatic compound, most preferably in toluene - and reacted with a formylating agent - preferably with an alkylformate, most preferably with n-butylformate - and the reaction product 17 is isolated.
In the subsequent cyclization reaction, in the eighth step of the process, the benzomorphan structure of type 18 is finally synthesized in the presence of correspondingly reactive Lewis acids - such as, for example, inorganic salt acids, particularly hydrobromic acid and preferably with sulfonic acids or with aluminium(III) halides, such as, e.g., aluminium trichloride.
The following reaction step results in the cleaving of the formyl group and thus produces the corresponding 4xe2x80x2-methoxy-5,9-dimethyl-6,7-benzomorphan 19. 
To do this the formylbenzomorphan 18 is dissolved in a polar solvent - preferably in an alkanol, most preferably in n-propanol - and combined with an acidically reacting compound - preferably with the aqueous solution of an inorganic acid, most preferably with concentrated hydrochloric acid - and then heated. After cleaving the formyl group, the reaction mixture is evaporated down, combined with water and extracted with a water-immiscible solvent - preferably with an ester of a carboxylic acid, most preferably ethyl acetate. The aqueous phase thus purified is made basic, preferably with concentrated ammonia solution, and extracted with an organic solvent - preferably with a halohydrocarbon, most preferably with dichloromethane. After drying and concentration by evaporation of the combined organic extracts, the corresponding (xe2x88x92)-4xe2x80x2-methoxy-5,9-dimethyl-6,7-benzomorphan 19 may be isolated, for example.
In this step, if this has not already been done, the stereoisomers which are still present as a mixture can be separated. The isolation may be effected using the methods described above or by methods known in the art for separating optical isomers.
In the following step the (xe2x88x92)-4xe2x80x2-methoxy-5,9-dimethyl-6,7-benzomorphan 19 thus obtained may be subjected to ether splitting under acidic conditions - preferably with an inorganic acid, e.g., with hydrohalic acid and most preferably with hydrobromic acid - resulting in the corresponding free partial phenol structure. 
The ether cleavage is carried out under acidic conditions; it has proved beneficial to use inorganic acids. The use of hydrobromic acid has proved particularly advantageous. The saponification product resulting from this saponification can be obtained in this way, for example, in the form of its hydrobromide.
Compound 5 is prepared by the reaction sequence shown in Diagram 4. 
The N-substituent is introduced by reacting the key compounds 2a to 5a with acylating agents to obtain the intermediate compounds 25 and subsequently reducing them or by directly alkylating the key compounds 2a to 5a with alkylating agents or by reacting with aldehydes to obtain 26 and subsequent reduction. Diagram 5 shows these methods for the key compound (xe2x88x92)-2a a by way of example. 
The compounds according to the invention can be synthesized by regioselectively substituting the aromatic benzomorphan species - using the methods known per se from the prior art. An example of the introduction of a substituent R3 according to general formula I is given for compound (xe2x88x92)-2b b in Diagram 6. 
Biological Properties
It has been found that cell damage and loss of function occurring as a result of hypoglycemia, hypoxia, anoxia and ischemia are due to increased synaptic activity to some extent. A series of experiments have demonstrated that hypoglycemic and hypoxic conditions of this kind lead to massive depolarization of the affected cells. This depolarization in turn causes a pathogenic rise in intracellular calcium and additionally causes an increased release of excitatory amino acids in the neuronal tissue. The voltage-dependent sodium channel has a key role in this cascade. Thus, blocking it can prevent the depolarization of the cells, thereby reducing the calcium influx through voltage-dependent calcium channels and in the neuronal tissue through NMDA-receptor channels. Furthermore, the reduced influx of sodium ions into the cell prevents the calcium/sodium exchanger from operating in the other direction and carrying calcium into the cell. In neuronal tissue the reduced influx of sodium ions into the cell also prevents the glutamate transporter from operating in the other direction and releasing glutamates [C. P. Taylor and B. S. Meldrum, TIPS 16 (1995) 309; J. Urenjak and T. P. Obrenovitch, Am. Soc. Phar. Exp. Ther. 48 (1996) 21].
Surprisingly, it has now been found that the compounds according to the invention of general formula I, unlike the compounds known from the prior art [EP-B-0 521422], have no appreciable affinities for the NMDA-receptor (Ki [3H] MK801:  greater than 10000 nM). On the contrary, it was found rather that the compounds according to the invention are blockers of the voltage-dependent sodium channel. These are compounds which competitively or non-competitively displace batrachotoxin (BTX) with a high affinity from the binding site on the sodium channel. Such substances exhibit xe2x80x9cuse-dependencyxe2x80x9d when the sodium channels are blocked, i.e., for binding the substances at the sodium channel, first of all the sodium channels have to be activated. Maximum blockage of the sodium channels is only achieved after repeated stimulation of the sodium channels. Consequently, the substances preferably bind to sodium channels which are multiply activated. As a result the substances are capable of activity preferentially in those regions of the body which are pathologically overstimulated.
BTX-binding to the sodium channel serves as a test system for detecting the sodium channel-blocking effect [S. W. Postma and W. A. Catteral, Mol. Pharmacol. 25, 219-224 (1984)], as do patch-clamp experiments which show that the compounds according to the invention block the electrically stimulated sodium channel in a xe2x80x9cuse-dependentxe2x80x9d manner [W. A. Catteral, Trends Pharmacol. Sci., 8, 57-65 (1987)].
Moreover, the compounds according to the invention are shown to have a neuroprotective effect by the blockade of veratridin-induced glutamate release [S. Villauneva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)]. Veratridine is a toxin which permanently opens up the sodium channel. This leads to an increased influx of sodium ions into the cell. By means of the cascade described above, this increased influx of sodium leads to an increased release of glutamate in the neuronal tissue. This increased release of glutamate can be antagonized with the compounds according to the invention.
Anticonvulsant properties of the substances according to the invention were demonstrated by their protective effect against spasms caused by the maximum electric shock in mice [M. A. Rogawski and R. J. Porter, Pharmacol Rev. 42, 223-286 (1990)] - neuroprotective properties were demonstrated by a protective effect in a rat-MCAO model [U. Pschorn and A. J. Carter, J Stroke, Cerebrovascular Diseases, 6, 93-99 (1996)].
There are also descriptions of sodium channel blockers being used to treat cyclophrenia (manic depressive disorder) [J. A. Calabrese, C. Bowden, M. J. Woyshville in: Psychopharmacology: The Fourth Generation of Progress (Eds.: D. E. Bloom and J. Kupfer) 1099-1111, Raven Press Ltd. New York]. These results demonstrate that the 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of general formula I can be used for treating diseases caused by dysfunction due to overstimulation. These include diseases such as arrhythmia, spasms, cardiac and cerebral ischemia as well as neurodegenerative disorders of various origins. For example, the following may be mentioned: epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, cerebral edema, cerebral stroke, perinatal asphyxia, amylotropic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarct, cardiac rhythm disorders, angina pectoris, pain, anesthesia and local anesthesia.
The following compounds have proved particularly effective in this context:
(xe2x88x92)-(1R,2xe2x80x3S)-2-(2xe2x80x3-benzyloxy)propyl-4xe2x80x2-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and
(xe2x88x92)-(1R,2xe2x80x3S)-2-[2xe2x80x3-(2xe2x80x2xe2x80x3,6xe2x80x2xe2x80x3-difluorobenzyl)oxy]-propyl-4xe2x80x2-hydroxy-5,9,9-trimethyl-6,7-benzomorphan.
The compounds according to the invention can be prepared from compounds known in the art, using the processes described in the following Examples, inter alia.
In particular the present invention relates inter alia to the following method of preparing norbenzomorphans of general formula 5, characterized in that
a) o-methoxychlorbenzylchloride 20 is reacted with the benzylpyridinium bromide 21 to obtain tetrahydropyridine 22 
and
b) the tetrahydropyridine derivative 22 is rearranged to obtain the N-benzylbenzomorphan derivative 23 
and
c) the amino nitrogen is debenzylated to obtain the methoxybenzomorphan derivative 24
and
d) the phenolether 24 and the benzomorphan derivative 5 are isolated 
In addition, the present invention relates to a process for preparing norbenzomorphans of general formula I 
wherein
a) a benzylcyanide of general formula 32 wherein R30 denotes a C1-C4-alkyl group, is subjected to the conditions of a Reformatsky reaction with a halocarboxylate of general formula 33, wherein R40 denotes C1-C8 -alkyl or benzyl, in the presence of an alkylhalosilane - preferably a trialkylchlorosilane and most preferably trimethylchlorosilane - and zinc powder in an inert solvent - preferably in an ether or in a halohydrocarbon and most preferably with dichloromethane and in the presence of a reducing agent which is selective with regard to the reduction of imino functions - preferably in the presence of an alkali metal borohydride derivative and most preferably in the presence of sodium cyanoborohydride - and the resulting carboxylic acid ester derivative of general formula 34 is isolated 
and
b) the carboxylic acid ester derivative of general formula 34 is subjected to the conditions of a Michael addition reaction with an acrylic acid ester, wherein the alcohol component R50 denotes a C1-C8-alkyl group or a benzyl group, in a solvent which is inert under the reaction conditions selected - preferably in an alkanol and most preferably in ethanol - and the resulting Michael addition product of general formula 35 is isolated 
and
c) the carboxylic acid diester derivative of general formula 35 thus prepared is subjected to the conditions of Dieckmann""s ester condensation in an inert solvent - preferably in an aliphatic or aromatic hydrocarbon and most preferably in toluene - in the presence of a basically reacting compound - preferably in the presence of an alkali metal alkoxide, a branched or unbranched C1-C4-alkanol and most preferably in the presence of potassium-tert-butoxide - and the resulting piperidone derivative of general formula 36 is isolated 
and
d) the piperidone derivative 36 is saponified and decarboxylated under acid or alkaline conditions, preferably in the presence of an alkali metal hydroxide or an inorganic acid and most preferably in the presence of sodium hydroxide, in a polar solvent or solvent mixture, preferably in a mixture of a straight-chained or branched C1-C4 alkanol and water and most preferably in an ethanol/water mixture, with heating, to obtain the corresponding piperidone ester derivative of general formula 37 which is isolated, and optionally the corresponding acid addition salt is prepared with an acid and isolated 
and
e) if desired, the mixture of stereoisomers thus obtained is dissolved in a reaction medium which is inert with regard to the enantiomer separation, optionally after the release of the enantiomeric free bases, combined with a suitable stereoisomer of an organic acid suitable for salt formation with a stereoisomer of the enantiomer mixture, the desired stereoisomer is isolated in the form of its addition salt with the optically active acid 
and
f) the pure stereoisomer 38xe2x80x2 or 38xe2x80x3 or the isomer mixture 38 thus obtained is subjected to a Wittig reaction after liberation from the enantiomerically pure acid addition salt in an inert solvent with a Wittig reagent generating a CH2=or CH3xe2x80x94CH=grouping, preferably with an ethyltriphenylphosphonium halide or with a methyltriphenylphosphonium halide, most preferably with methyltriphenylphosphonium bromide or ethyltriphenylphosphonium bromide in the presence of a basically reacting compound - preferably in the presence of an alkali metal alkoxide, most preferably potassium tert-butoxide - in an inert reaction medium - preferably in a cyclic ether, most preferably in tetrahydrofuran - and the reaction product of type 39 or the corresponding stereoisomer is optionally isolated in the form of its acid addition salt 
and
g) the alkene 39 obtained from the Wittig reaction is optionally first liberated from the acid addition salt thereof and the free base of type 39 is dissolved in an organic solvent - preferably in a halogenated hydrocarbon and most preferably in dichloromethane - and subjected to a formylation reaction at the piperidine nitrogen with a formylating agent - preferably n-butylformate - and the reaction product of type 40 or the corresponding stereoisomer is isolated 
and
h) the formyl compound 40 thus obtained - or the corresponding stereoisomer - is reacted with an inorganic acid or with a Lewis acid - preferably aluminium(III) chloride - dissolved in an inert solvent - preferably in a halogenated hydrocarbon and most preferably in dichloromethane - and the cyclization product of type 41 resulting from this reaction is isolated 
and
i) the benzomorphan derivative resulting from the cyclization reaction is dissolved in a polar solvent - preferably in a C1-C4-alkanol, most preferably in n-propanol - and reacted with an acidically reacting compound - preferably with the aqueous solution of an inorganic acid and most preferably with concentrated hydrochloric acid - and the deformylated norbenzomorphan of type 42 resulting from this reaction is optionally isolated in the form of its acid addition salt 
and
j) if the stereoisomers have not yet been separated, at this stage the stereoisomers are separated in a manner known per se and after the release of the free benzomorphan base the phenolether is cleaved with an acidically reacting compound - preferably with an inorganic acid and most preferably with hydrobromic acid - and the cleavage product of type 43 is isolated 
k) the cleavage product 43 is reacted with a compound of type Zxe2x80x94CHR8xe2x80x94Rxe2x80x2 wherein Z denotes a secondary amino substituted leaving group preferably a halogen such as chlorine, bromine, iodine or an organic sulfonate, preferably trifluoromethanesulfonate - and Rxe2x80x2 denotes xe2x80x94CR1R2XR7, 
or is reacted with a compound of type YC(O)Rxe2x80x2 wherein Y denotes a secondary amino nitrogen substituted leaving group, preferably a halogen such as chlorine, bromine, iodine or an organic sulfonate, preferably trifluoromethanesulfonate - and Rxe2x80x2 denotes xe2x80x94CR1R2XR7, and subsequently the carbonyl compound is reduced to the compound (xe2x88x92)-2xx as shown above 
or reacted with an aldehyde of general formula HC(O)xe2x80x94Rxe2x80x2 , wherein Rxe2x80x2 denotes - CR1Rp2XR7, and the resulting Schiff base 26 is reduced to the compound (xe2x88x92)-22xx as shown above 
and
l) optionally within the framework of an electrophilic substitution the substituent R3 is introduced 
Various other embodiments of the processes will be apparent to the skilled person from the present description. However, it is expressly pointed out that these Examples and the associated description are provided solely for the purpose of illustration and are not to be regarded as restricting the invention.
In addition, reference is expressly made to the contents of German Patent Application No. 197 40 110.4, from which the present application claims priority.